Evaluation of diverse α/β-backbone patterns for functional α-helix mimicry: analogues of the Bim BH3 domain

J Am Chem Soc. 2012 Jan 11;134(1):315-23. doi: 10.1021/ja207148m. Epub 2011 Dec 8.

Abstract

Peptidic oligomers that contain both α- and β-amino acid residues, in regular patterns throughout the backbone, are emerging as structural mimics of α-helix-forming conventional peptides (composed exclusively of α-amino acid residues). Here we describe a comprehensive evaluation of diverse α/β-peptide homologues of the Bim BH3 domain in terms of their ability to bind to the BH3-recognition sites on two partner proteins, Bcl-x(L) and Mcl-1. These proteins are members of the anti-apoptotic Bcl-2 family, and both bind tightly to the Bim BH3 domain itself. All α/β-peptide homologues retain the side-chain sequence of the Bim BH3 domain, but each homologue contains periodic α-residue → β(3)-residue substitutions. Previous work has shown that the ααβαααβ pattern, which aligns the β(3)-residues in a 'stripe' along one side of the helix, can support functional α-helix mimicry, and the results reported here strengthen this conclusion. The present study provides the first evaluation of functional mimicry by ααβ and αααβ patterns, which cause the β(3)-residues to spiral around the helix periphery. We find that the αααβ pattern can support effective mimicry of the Bim BH3 domain, as manifested by the crystal structure of an α/β-peptide bound to Bcl-x(L), affinity for a variety of Bcl-2 family proteins, and induction of apoptotic signaling in mouse embryonic fibroblast extracts. The best αααβ homologue shows substantial protection from proteolytic degradation relative to the Bim BH3 α-peptide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis Regulatory Proteins / chemistry*
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • Crystallography, X-Ray
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / chemistry*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • bcl-X Protein / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Mcl1 protein, mouse
  • Membrane Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein